Thyroid carcinoma
	The radiolabeled somatostatin analogue octreoscanİ is increasingly used among other things for the detection of endocrine tumors. Butler et al., Boston, MA, reported that in 2 patients with metastatic papillary carcinoma, that did not accumulate radioactive iodine, octreotide scanning revealed distant metastases that were not detected by CT-scanning. Although their experience is limited, these results indicate that the here reported technique may be used as an independent tool for staging metastatic papillary thyroid carcinoma. Daumerie et al., Brussels, Belgium, studied the prevalence of thyroid cancer in hot nodules. They studied retrospectively 93 patients with hot nodules of whom 52 were euthyroid, 11 hyperthyroid, and 30 subclinically hyperthyroid. The mean diameter of the hot nodule was 3 cm (range 1.5-6 cm). Based on pathological findings, two groups were discerned. Group I composed of 57 subjects in whom histological examination revealed a multinodular lesion, and group II composed of 46 subjects with a truly solitary nodule. A microcarcinoma (diameter <1 cm) was present in 2 patients of group I (4%) and 5 patients of group 2 (11%) with a total prevalence of 7.5% (7/93). The microcarcinoma was located in the nodule or in the capsule in 4 cases and outside the nodule, but in the same lobe, in 3 cases. According to the authors the results suggest that the probability of finding a malignant lesion in the presence of a hot nodule is far from negligible and should be taken into account in all therapeutic decisions, especially if the nodule has a diameter>3 cm. (Comment: The problem with these studies is that no control study is available i.e. the prevalence of microcarcinoma in patients without thyroid disease. Autopsy studies have been reported with a high prevalence of microcarcinoma and the biological significance of these tumors is not known. In other words, it is not known if these pathologically malignant tumors indeed have the biological potential of a carcinoma.) Chiu et al., Houston, TX, reviewed 127 cases, seen between 1950 and 1994 of patients with Hürthle (oxyphillic) cell neoplasms. Hürthle cell carcinomas are often considered to be different from follicular cell carcinomas because of more aggressiveness and early metastases both hematogenic and lymphogenic. In this group of 127 patients, 89 were considered having carcinomas and 38 adenomas by histological criteria. Many aspects were considered, for instance size of the tumor, ethnicity, gender distribution, multifocalicity of disease, extrathyroidal invasion, predominant sites of distant metastases, radioiodine ablation, cytostatic therapy, and external beam radiotherapy. The most important findings were that, within a follow-up of 4.8 years, 30% of patients with carcinoma died of this disease and none of the benign group. Cytostatic therapy (adriamycine) and external beam radiotherapy showed higher rates of disease- specific mortality than without treatment. It is concluded that Hürthle cell carcinoma is indeed an aggressive (sub)type of thyroid carcinoma and that no other therapy than primary surgery, improves patient outcome. Fine needle aspiration (FNA) cannot differentiate benign from malignant Hürthle cell neoplasm. Takiyama et al., Baltimore, MD, and Jacksonville, FL, previously found that Hürthle cell carcinoma have loss of heterozygosity (LOH) on chromosomal arms 1p and 2p that differs significantly from loss of heterozygosity in Hürthle cell adenoma. They tested if PCR-amplified DNA from FNA could be used to differentiate between Hürthle carcinoma and adenoma. They found indeed LOH seen in the FNA's to correspond to LOH seen in the Hürthle cell neoplasm and concluded that this techniques allow to distinguish between adenomas and carcinomas, rendering surgical management more optimal. Tallini et al., New Haven, CT, and New York, NY, tested the presence of mRNA for thyroid peroxidase (TPO) and thyroglobulin (TG) in peripheral blood samples (PBS) from 24 patients with thyroid carcinoma (18 papillary, 5 poorly differentiated, 1 anaplastic carcinoma), 20 patients with benign thyroid nodules and from 10 controls. In 13/24 both thyroid specific transcripts for TG and TPO were identified and in 2 additional cases TG mRNA alone was detectable. In the benign nodules TG mRNA was detected in 5/20 cases and TPO mRNA in 3/20 cases. The prevalence of positive mRNA for TPO and TG was significantly higher in carcinoma patients than in patients with benign thyroid nodules and in controls (p = 0.018 and 0.009 respectively). (Comment: For the moment these results are of too low sensitivity and specificity to be used in clinical practice.) Sherman et al., on behalf of the National Thyroid Cancer Treatment Cooperative Study (NTCTCS) Registry, reported outcome rates from a prospective multicenter study of the treatment of thyroid carcinoma. Staging of the tumor was done on the basis of patient age at diagnosis, tumor type, tumor size, intrathyroidal multifocality, extraglandular invasion, metastases, and tumor differentiation. By 1955, 1607 patients had been registered: 43% stage I, 24% stage II, 24% stage III, and 9% stage IV. Follow- up data were available on 1313 patients with a median follow-up of 13 months. After 100 months no patient had died stage I and II, about (as estimated from the presented graph) 15% of stage III, and about 19% of stage IV patients. The classification used, appeared to be useful for prediction of shortterm prognosis. The system can be used to identify patients that require more aggressive therapy. The staging requirements are available from routine clinical practice data. Also on behalf of the NTCTCS Registry Cooper et al., Baltimore, MD, Boston, MA, and Cincinnati, OH, prospectively enrolled and followed patients with papillary carcinoma since 1987 and evaluated if there was an influence of the serum TSH levels on the progression of disease. All patients were treated with T4. 667 Patients were followed for a mean period of 3.6 years and were staged at entry as low risk (n = 511) and high risk (n = 156) and then classified during follow-up as having no residual disease (n = 564), stable residual disease (n = 25), or progressive disease (n = 78). TSH was assessed annually and classified as ever if elevated, ever elevated or normal, always subnormal, or undetectable. Fewer high-risk patients ever had an elevated TSH (n = 7) compared to low-risk patients (n = 52) and fewer high-risk partients ever had an elevated or normal TSH (n = 40) compared to low-risk patients (n = 179). No relationship was found between disease progression and TSH levels, even in the high-risk patients. The authors suggest that maybe not in all patients protracted suppression of TSH to undetectable levels may be necessary. (Comment: I agree completely with the authors that these data are preliminary and that additional studies are needed with longer follow-up. One should realize that progression rate in papillary carcinoma is usually low and long follow-up time is absolutely necessary.) Taylor et al. also reported on behalf of the NTCTCS Registry. They investigated the effect of extent of surgery and of additional or no additional radioactive iodine in low and high risk patients with papillary and follicular carcinoma. In the papillary carcinoma patients high risk was based on a tumor over 4 cm in diameter, gross extraglandular invasion or neck node metastases. High risk follicular thyroid carcinoma patients had poor tumor differentiation, presence of distant metastases, were 50 years of age or older, had a tumor size of 1 cm or greater, multifocality, gross capsular invasion, or extraglandular invasion. High risk patients were followed for an average of 3.6 years and the most important results of this multicenter prospective study was, that survival was improved in papillary cancer patients after total/near total thyroidectomy. Improved survival, lack of progression, and improved disease free survival after radioiodine-131 was found for both high risk papillary and high risk follicular carcinoma patients. No improved prognosis was found of total/near total thyroidectomy in high risk follicular carcinoma patients. The conclusion is that more aggressive surgery and radioactive iodine treatment are warranted in high risk thyroid papillary carcinoma and that radioactive iodine improves prognosis in high risk follicular carcinoma patients. Colombo-Benkmann et al., Heidelberg and Berlin, Germany, tested cervical ultrasonography (US), CT scanning, selective venous catheterisation (SVC), and Methoxi- Iso-Butyl-Isonitrile-99mTc-scanning (MIBI) in 14 patients, all of whom were post-thyroidectomy and had at least undergone one previous cervical/mediastinal operation for tumor localization. All patients had elevated peripheral calcitonin-levels, but no systemic spread. They found that ultrasound and CT were almost identical regarding their diagnostic precision in identification of tumor localization (sensitivity and specificity 0.6/0.83 and 0.65/0.83 respectively). SVC was the least sensitive method but MIBI-scanning was the most sensitive and specific diagnostic tool (0.89/1.0). The authors conclude that, though the number of studied patients is yet small, MIBI- scanning may appear to be an advance in the detection of tumor localizations in this type of patients. Three reports on thyroid carcinoma in children were presented as a consequence of the Chernobyl Accident. Bogdanova et al., Kiev, Ukraine, Philadelphia, PA, and Toronto, Canada, reported that the incidence of thyroid carcinoma in children in the Ukraine, aged under 15, significantly increased between 6.5 and 10 times since the Chernobyl accident. Between 1986-1995, 256 cases were registered. The male to female ratio was 1-1.3, of which 93.6% was papillary, 2.9% follicular, and 3.5% medullary carcinoma. In the papillary group 32.4% were of the solid variant, characterized by more aggressiveness i.e. intraglandular spread 68%, soft tissue infiltration 79%, lymphatic invasion 91%, blood vessel infiltration 29%, and lymphnode invasion 76%. Psammoma bodies were present in 88%. Ashizawa et al., Nagasaki, Japan, examined 150,000 children in Belarus, Russian Federation and Ukraine. Echo-guided FNAB was performed in lesions larger than 5 mm, and 125 children were biopsied for such nodular lesions. A cytological diagnosis was possible in 93%. 24 (19%) papillary carcinomas were detected and 1 medullary carcinoma. All diagnoses were confirmed upon histological examination after operation. The other cytological diagnoses were: 22% follicular neoplasms, and 28% benign adenomas. In 11 cases cytological signs for autoimmune thyroiditis were found. Vorontsova et al., Minsk, Belarus, measured T-cell subsets: CD3, CD4, and CD8 in 240 children between 5-15 years with thyroid carcinoma (96% papillary) and found that T-subcell indices were depressed in children with tumor stages N1M0 and N1M1 as compared to N0M0. They also found that this depression was more severe in the same stage groups that were treated with radioactive iodine as compared to no radioactive iodine. The authors suggest that spread of tumor depresses the immune system as does treatment with radioactive iodine. (Comment: The big question, of course is, if the depressed T-cell subsets are a consequence of tumor spread or the reverse, that is that a depressed immune system by any other reason allows spread of the tumor.) Schneider et al., Chicago, IL, did a study to determine the role of thyroid ultrasonography in the follow-up of 54 subjects who received conventional radiation of the head and neck area during childhood. Three independent observers interpreted the thyroid scans. During the first screening in 1974-1976 thyroid scintigraphy was normal and no palpable nodules were present. At the present (second) screening in 47 subjects (87%), ultrasound showed in total 157 nodules, 40 of which were ü 10 mm, occurring in 28 (52%) of the subjects. In 26/28 of these subjects additional smaller nodules were found and these smaller nodules were the only finding in 19 subjects. The mean size of the large vs. small nodules was 13.7 vs. 5.1 mm respectively. Only 26/40 (65%) of the large nodules were detected on thyroid scintigraphy and of the small nodules (n = 117) only 21% was found on the thyroid radionuclide scan. The authors conclude that nodules are continuing to occur in irradiated individuals. They caution, however, for overinterpretation and overtreatment of patients with detected nodules as the biological significance (malignant growth or not) is not known as yet. (Comment: I agree completely with the fact that one should be very prudent in the interpretation of the biological meaning of a nodule that is present on the thyroid ultrasound, certainly if it is small one. It would be very interesting if the authors would have followed a control group in the same manner to evaluate the difference in nodule formation between irradiated and non-irradiated subjects.) Sabanci et al., San Francisco, CA, published the simultaneous occurrence of medullary and papillary carcinoma in 3 females and 1 male with a median age of 44 years. This number has to be added to the already 7 similar patients reported in the literature. The medullary cancer appears to be more aggressive than the papillary component. Radioactive iodine beneficially affects the papillary component, but not the medullary component. In 1 patient both the medullary carcinoma and the papillary carcinoma were familial. (Comment: Unfortunately no oncogene analysis was done in this family, but see below.) McIver et al., Rochester, MN, published another patient with a mixed papillary-medullary thyroid carcinoma from a family with multiple endocrine neoplasia type 2B (MEN-2B). Here oncogene analysis was performed and a germline mutation was found in codon 918 of the RET proto-oncogene. The authors performed a search in the Mayo Clinic database from 1970-1995 and two other true mixed medullarypapillary thyroid carcinoma cases were found. One of these cases was associated with MEN-2A and the other with a strong family history of von-Hippel-Lindau syndrome. RET oncogene data were not available in these two cases. The authors stated that 4 cases of mixed papillary-medullary carcinoma, reported in the world literature, originate from family diseases associated with RET oncongene mutations. Yin et al., Beijing, China, studied the concentration of CD9 expression in 138 patients with papillary thyroid carcinoma. CD9 which is identical to motility-related protein- 1 and regulates cell motility. They found CD9 expression to be reduced in 45/138 patients. In these 45 patients prognosis as based on disease free survival and overall survival rate, was poor as compared to the other patients with normal CD expression. A similar study i.e. with regard to markers that may predict prognosis of thyroid tumors was reported by Haugen et al., Denver, CO. These authors measured telomerase activity in 15 malignant and 4 benign thyroid tumors. Telomerase is a ribonucleoprotein synthesizing telomeric DNA onto chromosome ends. It is mostly absent in mortal cells but present in immortal cells and thought to be essential for malignant growth. Of the 15 malignant nodules, 11 were of papillary type and in 7 (64%) telomerase activity was detected. This was absent in the other malignant tumors and in the benign tumors. It is stated that the assay could be theoretically done on only 100 cells and the technique is thus suitable to be used in thyroid cytology. Messina et al., Rome, Italy, evaluated Colour-Flow Doppler Sonography (CFDS) and ultrasonography (US) in patients with thyroid carcinoma. In 220 cases, undergoing surgery for carcinoma, preoperative US was performed and CFDS in 56/220 cases. Their data show that in thyroid carcinoma an inhomogeneous-hypoechoic solid nodule with internal calcifications is the most frequent pattern on US, whereas in these patients an intra- and perinodular vascularization with a higher arterial flow is found with CFDS. They underline that these features are by itself not sufficient to establish the diagnosis of malignancy as these signs may be also present in benign lesions. (Comment: These data are preliminary and are still considered to be experimental.)